Sonic Hedgehog Pathway Activation Is Associated With Resistance to Platinum-Based Chemotherapy in Advanced Non–Small-Cell Lung Carcinoma

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Abstract

Micro-Abstract

Of the patients with advanced non–small-cell lung cancer, 30% will have disease refractory to platinum-based chemotherapy. We investigated the role of the Sonic hedgehog (Shh) pathway in patients with refractory disease. These patients had higher Gli2 expression than that of other patients. Gli2 expression independently correlated with progression-free survival and overall survival. Shh pathway inhibition had a synergistic effect in vitro with cisplatin.

Introduction:

Chemoresistance is a major challenge in the treatment of advanced non–small-cell lung cancer (NSCLC). Because the Sonic hedgehog (Shh) pathway is reactivated in NSCLC, we investigated an association between chemoresistance and Shh activation.

Patients and Methods:

From a cohort of 178 patients with advanced NSCLC treated with platinum-based chemotherapy as first-line treatment, we selected all surgical tumor samples at diagnosis (n = 36). Shh activation was evaluated through Gli1 and Gli2 expression using immunohistochemistry (quantitative score). In vitro treatment studies with cisplatin or vismodegib (Shh pathway inhibitor), or both, were performed on NSCLC cell lines (H322 and A549) and primary cultures from patients with sarcomatoid carcinoma (n = 4).

Results:

Of the 36 patients, 12 had NSCLC refractory to chemotherapy (R-patients, 33.3%) and 24 had controlled disease (C-patients). Gli1 expression did not differ between the R- and C-patients (P = .35). Gli2 expression was more often positive in the R-patients (41.7% vs. 8.3%; P = .02). Progression-free survival (PFS) and overall survival (OS) in patients with a Gli2-positive score was 2.1 and 8.0 months, respectively, compared with 6.7 and 18.0 months for patients with a Gli2-negative score (P = .03 and P = .002, respectively). On multivariate analysis, the Gli2 score correlated independently with PFS (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.05-6.63; P = .04) and OS (HR, 4.36; 95% CI, 1.67-11.36; P = .003). The sarcomatoid carcinoma cell lines were more resistant to cisplatin than were the H838 and A549 cell lines. The cisplatin-vismodegib combination displayed a synergistic cytotoxic effect in the most chemoresistant cells in vitro.

Conclusion:

The Shh pathway is associated with resistance to platinum-based chemotherapy in NSCLC.

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